Pregabalin is an analog of γ-aminobutyric acid (Gamma-aminobutyric acid, GABA). Its chemical name is (S)-3-(aminomethyl)-5-methylhexanoic acid, its molecular equation is C8H17NO2, and its molecular weight is 159.23.
U.S. Pat. No. 5,563,175 discloses that γ-aminobutyric acid is useful as antiseizure therapy for central nervous system disorders such as epilepsy, Huntington's chorea, cerebral ischemia, Parkinson's disease, tardive dyskinesia, and the like, and U.S. Pat. No. RE 41,920 discloses that isobutylgaba, glutamic acid and γ-aminobutyric acid, which are derivatives of isobutylgaba, are effective in pain therapy against hyperalgesic and allodynic actions.
Pregabalin is a white or pale yellow crystalline powder, which has a water-soluble property. Pregabalin is bonded to an alpha-2-delta (α2δ) subunit of a calcium channel in the central nerve, and is involved in the regulation of neurotransmitter (γ-aminobutyric acid) activity, and this is used for the treatment of peripheral and central neuropathic pain, epilepsy, fibromyalgia, etc. When pregabalin is orally administered with between 1 and 600 mg, the absorption amount is dose-dependent, the maximum blood level arrival time (Tmax) is between 0.8 to 1.2 hours, and the half-life of a drug is between 5.2 to 6.6 hours. At present, pregabalin has been commercially available in oral capsule products (product name: Lyrica Capsule, Pfizer) that can be administered twice daily at a daily dose of from 150 mg up to 600 mg at maximum, and this can be used only as immediate release formulations.
However, drugs that are administered twice daily or three times daily are inconvenience for patients who take the drugs. Compliance to elderly patients or patients who take drugs for a long time is greatly reduced.
Since pregabalin can be used only in formulations that can be administered twice daily, this is inconvenient in terms of compliance.
If the drug administration method is changed to be administered once daily through the preparation development, there are following advantages that: compliance to patients will be greatly improved; drug concentration in blood can be maintained constantly, thereby reducing or preventing undesired dose-dependent side effects; and drug efficacy can be maintained continuously.
Especially, it has been known that for first administration, pregabalin can be administered twice daily and its dose can be gradually increased from 75 mg for one time up to 600 mg for day at maximum at an interval of 7 days, and the arrival time to a drug steady-state takes 24 to 48 hours after first intake.
Herein, if the dose is gradually increased while observing a drug reaction shown when taking a drug with accurately complying with the dose having high compliance through the method such as an administration once daily, more accurate final dose can be determined in terms of safety and efficiency. This is because, if compliance is low, the dose is not accurate, and thus the final dose which is determined by increasing the dose while observing the drug reaction may be inaccurate.
According to existing clinical studies, it has been known that pregabalin is not absorbed homogeneously in the gastrointestinal tract, and that most of drugs are absorbed by an L-amino acid transporter in the upper portion of the gastrointestinal tract. Therefore, the absorption occurs mainly in the small intestine and the ascending colon, and if the drugs pass through the hepatic flexure, the drugs are hardly absorbed.
It has been known that conventional sustained-release tablets pass through the hepatic flexure at about 6 hours after the administration. Thus, in the case of developing sustained-release tablets containing pregabalin, the tablets will pass through the hepatic flexure at about 6 hours after the administration. However, since pregabalin is hardly absorbed in the hepatic flexure, the drug release of the general pregabalin-containing sustained-release tablets after 6 hours is not clinically significant. As such, since there is a limitation of time when pregabalin is absorbed in the body after the administration, there is a problem in developing formulations that can be administered once daily.